Sjogren's syndrome (SjS), an autoimmune disorder, targets mainly the salivary and lacrimal glands, resulting in dry mouth and dry eye symptom, respectively. Despite recent numerous studies to understand the disease pathogenesis, the exact mechanism for secretory dysfunction in SjS is not currently available. We have shown that autoantibodies targeting muscarinic 3 receptor (M3R) are capable of inducing dryness by transferring purified serum IgG or F(ab')2 fragments from disease-prone non-obese diabetic (NOD) mice or human primary SjS patients into the B-cell deficient NOD.Igu null mouse. Furthermore, we proved that the NOD.IL-4 KO mouse does not lose secretory function despite all disease-associated phenotypic changes except for the absence of lgG1anti-M3R autoantibodies, suggesting lgG1 isotypic function is critical to secretory dysfunction in the NOD mouse. Therefore, to understand the exact role of lgG1 directing M3R, we posit that the importance of lgG1 is not necessarily within the premise of its classical effector functions of constant region but resides in its variable region whose fine specificity is shaped by lgG1 isotype (presumably, lgG4 in humans). In this R21 application, we propose to investigate three Specific Aims: Specific Aim 1: Determine if loss of secretion in SjS is dependent on isotypic autoantibodies, especially lgG1 anti-mouse anti-M3R autoantibodies (lgG4 in humans). Specific Aim 2: To investigate if the effect of isotypic antibodies in secretory dysfunction is initiated by altered intracellular calcium release independent of constant region of lgG1 anti-mouse M3R autoantibodies (lgG4 in humans). Specific Aim 3: Determine if altered intracellular calcium release by binding of lgG1 anti-mouse M3R autoantibodies (lgG4 in humans) to the receptor blocks the translocation of aquaporin 5 to the plasma membrane, thus leading to loss of secretion in SjS. If our hypotheses are proven to be correct, the priority of SjS research will be given to the epitope mapping of M3R for the development of diagnostic and therapeutic strategies to restore secretory capacity in SjS patients.